Parkinson's disease is widely considered to be the result of degradation of the pre-synaptic dopaminergic neurons in the brain, with a subsequent decrease in the amount of the neurotransmitter dopamine, that is being released. Inadequate dopamine release, therefore, leads to the onset of voluntary muscle control disturbances symptomatic of Parkinson's disease.
Various procedures for treating Parkinson's disease have been established and are currently in widespread use, for example, the administration of L-Dopa, which is a precursor of dopamine, together with a decarboxylase inhibitor, such as L-carbidopa or benzerazide. The decarboxylase inhibitor protects the L-Dopa molecule from peripheral decarboxylation and thus ensures L-Dopa uptake by the remaining dopaminergic neurons in the striatum of the brain. Here the L-Dopa is converted into dopamine resulting in increased levels of dopamine in these neurons. In response to physiological impulses these neurons are therefore capable of releasing larger amounts of dopamine, the quantity of which approximates the normal required levels. This treatment therefore alleviates the symptoms of the disease and contributes to the well-being of the patients.
However, this L-Dopa treatment has its drawbacks, the main one being that its effectiveness is optimal only in the first few years following the onset of treatment. After this initial period the clinical response is diminished and is accompanied by adverse side effects which include dyskinesia, fluctuation in efficacy throughout the day "on-off effect") and psychiatric symptoms such as confusional states, paranoia and hallucinations. This fall-off in the effect of L-Dopa treatment is attributed to a number of factors, including the natural progression of the disease, alteration in dopamine receptors as a consequence of increased dopamine production or increased levels of dopamine metabolites, and pharmacokinetic problems of L-Dopa absorption (reviewed by Youdim et at., Progress in Medicinal Chemistry, Vol. 21, Chapter 4, pp. 138-167 (1984), Eds. Ellis and West, Elsevier, Amsterdam).
In order to overcome the drawbacks of the L-Dopa treatment, various treatments have been devised in which L-Dopa is combined with MAO inhibitors, with the aim of reducing the metabolic breakdown of the newly formed dopamine (see for example, U.S. Pat. No. 4,826,875).
MAO exists in two forms known as MAO-A and MAO-B which have selectivity for different substrates and inhibitors. For example, MAO-B metabolizes more efficiently substrates such as 2-phenylethylamine and is selectively and irreversibly inhibited by (-)-deprenyl (as described below).
It should be noted, however, that combining L-Dopa with an inhibitor of both MAO-A and MAO-B is undesirable leading to adverse side effects related to an increased level of catecholamines throughout the neuraxis. Furthermore, complete inhibition of MAO is also undesirable as it potentiates the action of sympathomimetic amines such as tyramine leading to the so-called "cheese effect" (reviewed by Youdim et al., Handbook of Experimental Pharmacology, Vol. 90, Chap. 3 (1988) Eds, Trendelenburg and Weiner, Springer-Verlag). As MAO-B was shown to be the predominant form of MAO in the brain, selective inhibitors for this form were thus considered to be a possible way for achieving a decrease in dopamine breakdown on the one hand, together with a minimization of the systemic effects of total MAO inhibition, on the other.
One of these selective MAO-B inhibitors, (-)-deprenyl, has been extensively studied and has been used as an MAO-B inhibitor to augment L-Dopa treatment. This treatment with (-)-deprenyl is generally favourable, not causing the "cheese effect" at doses causing nearly complete inhibition of MAO-B (Elsworth et al., Physchopharmacology, 57, 33 (1978). Furthermore, addition of (-)-deprenyl to a combination of L-Dopa and decarboxylase inhibitor to Parkinson's patients leads to improvements in akinesia and overall functional capacity as well as the elimination of "on-off" type fluctuations (reviewed by Birkmayer & Riederer in "Parkinson's Disease" pp. 138-149, Springer-Verlag (1983)).
Thus, (-)-deprenyl enhances and prolongs the effect of L-Dopa and permits a lowering of the dosage of L-Dopa whereby the adverse effects of L-Dopa treatment are limited.
A more potent selective inhibitor of MAO-B than the racemic mixture is the optical isomer R-(+)-N-propargyl-1-aminoindan. HCl [R-(+)-PAI.HCl] which is more selective in vivo and in vitro as described in our copending Israel Patent Application No. 92952.
However it is highly desirable to further increase the selectivity of MAO inhibitor, inhibiting preferably MAO-B and not MAO-A, thus minimizing the side effects caused by the inhibition of MAO-A.
The compounds of the present invention were found to have a surprisingly high degree of selectivity in vitro, inhibiting preferably MAO-B over MAO-A.
The compounds of the present invention are mono-fluoro derivatives of N-propargyl-1-aminoindan stereoisomers and salts thereof.
U.S. Pat. No. 3,513,244 claims generically and specifically a large number of secondary and tertiary aminoindans which are stated to have hypotensive activity. There is no disclosure of the specific compounds of the present invention, and there is no evidence that the mono-fluorinated derivatives of 1-propargylaminoindan of the present invention have ever been synthesised and characterised. Furthermore, the secondary and tertiary aminoindans of U.S. Pat. No. 3,513,244 are stated to have hypotensive activity and there is no teaching that any components of the group have any as MAO-B inhibitor activity.
British Patent No. 1,003,686 discloses a group of benzocycloalkane compounds in which the cycloalkane has from five to seven ring members and is substituted by an N-(alkynylalkyl)amino group. This patent mentioned the possibility of substituting the aromatic portion of the benzocycloalkane ring system by one or more halogen atoms. Although the compounds of the present invention are generically included in the group, they are not specifically disclosed. The compounds claimed in British Patent No. 1,003,683 are stated to be monoamine oxidase inhibitors in general, but there is no disclosure of any activity by which MAO-B is inhibited, selectively in preference over MAO-A.
The mono-fluorinated N-propargyl-1-aminoindans of the present invention are surprisingly more potent selective MAO-B inhibitors than any of the other species of the groups disclosed in both U.S. Pat. No. 3,513,244 and British Patent No. 1,003,686, enabling the inhibition of MAO-B at lower concentrations. This high potency and selectivity in vivo is a unique and surprising property of the mono-fluorinated N-propargyl-1-aminoindan compounds and their salts according to the invention, not shared by other halogenated N-propargyl-1-aminoindans.
The MAO-B inhibitors of the present invention can also be used for the treatment of patients with dementia of the Alzheimer type (DAT), and the treatment of patients with depression and for treatment of hyperactive syndrome in children. Other MAO-B inhibitors have been used in the past for the treatment of patients suffering from these diseases (Tariot et al., Psychopharmacology, 91, 489-495, 1987), J. Mendlewich and M. B. H. Youdim (Brit. J. Psychiat., 142, 508-511, 1983, Perenyi A., et al., PCT/HU89/00044, 17 Aug. 1988).